Oleic Acid Dissolves cGAS–DNA Phase Separation to Inhibit Immune Surveillance DOI Creative Commons
Lina Wang, Qiaoling Liu, Na Wang

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(14)

Published: March 22, 2023

Phase separation (PS) is a fundamental principle in diverse life processes including immunosurveillance. Despite numerous studies on PS, little known about its dissolution. Here, it shown that oleic acid (OA) dissolves the cyclic GMP-AMP synthase (cGAS)-deoxyribonucleic (DNA) PS and inhibits immune surveillance of DNA. As solvent components control metabolites are abundant cellular components, speculated some metabolite(s) may dissolve PS. Metabolite-screening reveals cGAS-DNA condensates formed via markedly dissolved by long-chain fatty acids, OA. OA revokes intracellular cGAS-PS DNA-induced activation. attenuates cGAS-mediated antiviral anticancer These results link metabolism immunity dissolving which be targeted for therapeutic interventions.

Language: Английский

Liquid–liquid phase separation in tumor biology DOI Creative Commons

Xuhui Tong,

Rong Tang, Jin Xu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 8, 2022

Abstract Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response repair, transcription, signal transduction. Dysregulation these cellular processes key event initiation and/or evolution cancer, emerging evidence has linked formation to malignant transformations tumor biology. In this review, we comprehensively summarize detailed mechanisms condensate biophysical function review recent major advances toward elucidating multiple involved cancer cell pathology driven by aberrant LLPS. addition, discuss therapeutic perspectives research most developed drug candidates targeting modulation that can be used combat tumorigenesis.

Language: Английский

Citations

136
Interaction modules that impart specificity to disordered protein DOI Creative Commons
Kateřina Čermáková, H. Courtney Hodges

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(5), P. 477 - 490

Published: Feb. 6, 2023

Intrinsically disordered regions (IDRs) are especially enriched among proteins that regulate chromatin and transcription. As a result, mechanisms influence specificity of IDR-driven interactions have emerged as exciting unresolved issues for understanding gene regulation. We review the molecular elements frequently found within IDRs confer regulatory specificity. In particular, we summarize differing roles low-complexity (LCRs) short linear motifs (SLiMs) towards selective nuclear Examination highlights SLiMs organizers selectivity, with widespread in regulation integration cellular signals. Analysis recurrent between folded domains suggests diverse avenues to phase-separated condensates opportunities manipulate these control biological activity.

Language: Английский

Citations

49
The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis DOI Creative Commons

Shuolin Liu,

Yaguang Bi,

Tianting Han

et al.

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 27, 2024

Inflammasome activation and pyroptotic cell death are known to contribute the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although underlying regulatory mechanisms remain poorly understood. Here we report that expression levels E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse upon I/R injury. Genetic ablation MARCH2 aggravated infarction cardiac dysfunction Single-cell RNA-seq analysis suggested loss prompted NLRP3 inflammasome cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found act a novel regulator MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS fostering recruitment NLRP3. directly interacts PGAM5 promote its K48-linked polyubiquitination proteasomal degradation, resulting reduced PGAM5-MAVS co-condensation, consequently inhibition cardiomyocyte pyroptosis. AAV-based re-introduction significantly ameliorated I/R-induced heart dysfunction. Altogether, our findings reveal mechanism where MARCH2-mediated ubiquitination negatively regulates PGAM5/MAVS/NLRP3 axis protect against pyroptosis

Language: Английский

Citations

32
Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life DOI Creative Commons
Dominik Lewandowski, Christopher L. Sander, Aleksander Tworak

et al.

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 89, P. 101037 - 101037

Published: Dec. 29, 2021

The retinal pigment epithelium-photoreceptor interphase is renewed each day in a stunning display of cellular interdependence. While photoreceptors use photosensitive pigments to convert light into electrical signals, the RPE supports their function by phagocytizing shed photoreceptor tips, regulating blood retina barrier, and modulating inflammatory responses, as well regenerating 11-cis-retinal chromophore via classical visual cycle. These processes involve multiple protein complexes, tightly regulated ligand-receptors interactions, plethora lipids protein-lipids interactions. role maintaining healthy interplay between has not been fully delineated. In recent years, novel technologies have resulted major advancements understanding several facets this interplay, including involvement phagocytosis phagolysosome function, nutrient recycling, metabolic dependence two cell types. review, we aim integrate complex emphasizing dynamic exchange cells discuss how these are affected aging diseases.

Language: Английский

Citations

63
Phase separation in viral infections DOI
Haohua Li, Christina Ernst, Marta Kolonko

et al.

Trends in Microbiology, Journal Year: 2022, Volume and Issue: 30(12), P. 1217 - 1231

Published: July 25, 2022

Language: Английский

Citations

57
Kinase regulation by liquid–liquid phase separation DOI Creative Commons

Tania P. López-Palacios,

Joshua L. Andersen

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(8), P. 649 - 666

Published: Dec. 15, 2022

Liquid–liquid phase separation (LLPS) is emerging as a mechanism of spatiotemporal regulation that could answer long-standing questions about how order achieved in biochemical signaling. In this review we discuss LLPS orchestrates kinase signaling, either by creating condensate structures are sensed kinases or direct kinases, cofactors, and substrates – thereby acting to compartmentalize kinase–substrate relationships, some cases also sequestering the away from inhibitory factors. We examine possibility selective pressure promotes genomic rearrangements fuse pro-growth LLPS-prone protein sequences, which turn drives aberrant activation through LLPS.

Language: Английский

Citations

57
Phase separation of SGS3 drives siRNA body formation and promotes endogenous gene silencing DOI Creative Commons
Huijuan Tan,

Wentao Luo,

Wei Yan

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 111985 - 111985

Published: Jan. 1, 2023

The generation of small interfering RNA (siRNA) involves many processing components, including SUPPRESSOR OF GENE SILENCING 3 (SGS3), RNA-DEPENDENT POLYMERASE 6 (RDR6), and DICER-LIKE proteins (DCLs). Nonetheless, how these components are coordinated to produce siRNAs is unclear. Here, we show that SGS3 forms condensates via phase separation in vivo vitro. interacts with RDR6 drives it form siRNA bodies cytoplasm, which promoted by SGS3-targeted RNAs. Disrupting abrogates body assembly biogenesis, whereas coexpression induces formation tobacco yeast cells. Dysfunction translation mRNA decay increases the number bodies, DCL2/4 mutations enhance their size. Purification identifies numerous RNA-binding components. Together, our findings reveal separation-mediated essential for production gene silencing.

Language: Английский

Citations

30
BRD4-targeting PROTAC as a unique tool to study biomolecular condensates DOI Creative Commons
Yi Shi,

Yuan Liao,

Qianlong Liu

et al.

Cell Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: May 9, 2023

Biomolecular condensates play key roles in various biological processes. However, specific condensation modulators are currently lacking. PROTAC is a new technology that can use small molecules to degrade target proteins specifically. expected regulate biomolecular dynamically by degrading/recovering condensates. In this study, we employed BRD4-targeting molecule the super-enhancer (SE) condensate and monitored changes of SE under treatment using live-cell imaging high-throughput sequencing technologies. As result, found PROTACs significantly reduce BRD4 condensates, established quantitative method for tracking cellular imaging. Surprisingly encouragingly, were observed preferentially form specialized process regulation first time. Additionally, makes it possible observe dynamics other components continued disruption Together, these results shed light on research methods liquid-liquid phase separation (LLPS), specifically demonstrate presents powerful distinctive tool study

Language: Английский

Citations

28
Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response DOI Creative Commons
Kazuhiro Morishita, Kengo Watanabe, Isao Naguro

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112315 - 112315

Published: April 1, 2023

Biomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular crucial for their biological functions and pathogenicity. However, maintenance in cells remains elusive. Here, we show sodium ion (Na+) influx regulates condensate liquidity under hyperosmotic stress. ASK3 higher fluidity at high intracellular Na+ concentration derived from extracellular solution. Moreover, identified TRPM4 as a cation channel allows inhibition causes liquid-to-solid transition condensates, leading to impairment osmoresponse. In addition widely aggregate formation biomolecules, including DCP1A, TAZ, polyQ-protein, Our findings demonstrate changes contribute cellular stress response via condensates.

Language: Английский

Citations

23
High-throughput and proteome-wide discovery of endogenous biomolecular condensates DOI
Pengjie Li, Peng Chen, Fukang Qi

et al.

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(7), P. 1101 - 1112

Published: March 18, 2024

Language: Английский

Citations

16